Immunosuppressant Drugs
The key issue of the transplantation field is to suppress the immune responses leading to graft rejection. Thus, the development of immunosuppressive drugs capable of selectively and effectively regulating immune responses specific to grafts is a key issue to increase the success rate of transplantation. T cells are the major target to prevent the transplant rejection, and most immunosuppressive drugs clinically used inhibit the T cell responses.
Azathioprine is the first immunosuppressant used in organ transplantation. However, azathioprine inhibits DNA synthesis, resulting in side effects such as leukopenia, bone marrow suppression and macrocytosis, and thus was converted to a second-line therapy after the introduction of cyclosporine. Cyclosporine and tacrolimus, which are calcineurin inhibitors, are currently being used as first-line therapy in organ transplantation.
The two drugs block the expression of interleukin-2 (IL-2) by inhibitoin of calcineurin. Further, these drugs can suppress the T cell activation in the initial stage, and thus strongly suppress the immune responses leading to graft rejection. However, these drugs are required to be administered over a long period and cause side effects, including nephrotoxicity, anemia and hypertension, as well as infectious diseases and tumors caused by a weakening in the immune system. In recent years, in order to reduce the side effects of the calcineurin inhibitors, mycophenolate mofetil that is an inhibitor of nucleotide synthesis has been administered in combination with the calcineurin inhibitor, but has shown side effects such as digestive disease, leukopenia and anemia.
Sirolimus and everolimus, which are inhibitors of mTOR (mammalian target of rapamycin), are drugs that inhibit the proliferation of T cells by blockade of IL-2 receptor signaling. These drugs are mainly administered in combination with the calcineurin inhibitor, because the efficacy is mild when these are administered alone. However, these drugs increase the side effects of the calcineurin inhibitor, such as hyperlipidemia and thrombocytopenia.
FTY720, an antagonist of sphingosine-1-phosphate, is a drug that reduces immune responses by blocking the T cell migration from lymphoid organs to grafts, and has an advantage of low toxicity compared to other drugs. However, FTY720 can cause heart attack when it is administered with other drugs (e.g., general anesthetics and beta-blockers). In the organ transplantation field, combination therapy with cyclosporine is in clinical trials (see N Engl J Med. 351, 2715-2729; N Engl J Med. 352, 1371-1373; Nat Med. 11, 605-613; Business Insights. 2010, BI100022-067).
As described above, the current immunosuppressants for preventing transplant rejection are toxic and cause many side effects such as the occurrence of infection and tumors by weakening the immune system. Thus, the development of new drugs capable of selectively depleting T cells that respond to transplantation antigens is required.
Graft-Versus-Host Disease
Allogeneic haematopoietic stem cell transplantation (HSCT) is the most effective and permanent treatment method for various malignant blood diseases and immune deficiency diseases and is being used for treatment of about 20,000 or more patients annually worldwide (as reported by the Center for International Blood and Marrow Transplant Research). In recent years, the application of the HSCT to autoimmune diseases, solid cancers and the organ transplantation field has been attempted. Despite the rapid development of allogeneic haematopoietic stem cell transplantation (e.g., the development of HLA identification technology and new immunosuppressants) during the past 20 years, graft-versus-host disease (GVHD) that is a complication caused by donor T cells still remains as the major cause of post transplantation mortality. Acute GVHD (grades II-IV) that occurs mainly before 100 days after transplantation appears in 25-60% of the patients in the case of HLA matching between blood relations and 45-70% of the patients in the case of non-blood relation, and 70% or more of patients with the disease (grades III-IV) die. Acute GVHD develops in three stages. In the first stage, proinflammatory factors (TNF-α and LPS) produced by high-dose chemotherapy and systemic radiotherapy before transplantation, activate the dendritic cells of peripheral lymphoid organs. In the second stage, alloantigen-specific T cells proliferate by activated dendritic cells and differentiate into effector cells. In the final stage, the alloantigen-specific effector T cells migrate the gut, the liver and the skin, which are major target organs, and cause inflammatory injury to tissues.
The response rate of the calcineurin inhibitor that is a first-line therapy for preventing acute GVHD is about less than 50%, and thus the prevention rate is very low compared to that of organ transplantation. Treatment after GVHD development depends on steroid therapy, but the steroid therapy shows a response rate of less than 50%, and thus is classified as high-risk therapy having high therapy-related mortality (see Annu Rev Immunol. 25, 139-170; Blood. 114, 4327-4336; Lancet. 373, 1550-1561, Curr Opin Immunol. 11, 509-515). Thus, the development of new effective drugs for the prevention and treatment of acute GVHD is urgently required.
Multiple Sclerosis
Multiple sclerosis is an inflammatory disease of the central nervous system (CNS), which is an autoimmune disease caused by T cells reacting to the myelin-derived antigen. It shows a relapse-remitting pattern in the initial stage of development, and then progresses into secondary progressive multiple sclerosis due to the progressive accumulation of brain and spinal cord lesions. The accumulation of brain and spinal cord lesions leads to visual loss, movement and balance disorders, language and sensory disorders, paraplegia, sexual function impairment, and disturbances of urination and evacuation, and when the accumulation is severe, it causes systemic paralysis.
Therapies for treating multiple sclerosis are largely divided into management of acute exacerbations, disease-modifying therapy, symptomatic therapy, and preventive therapy. The management of acute exacerbations are performed to weaken inflammation and provide immunosuppressant effects, and the disease-modifying therapy is performed to retard the progression of the disease so as to prevent the disease from developing into progressive multiple sclerosis.
In the management of acute exacerbations, a high dose (500-1000 mg/kg) of glucocorticoid is administered intravenously for 3-5 days in order to alleviate the symptoms and prevent permanent injury. Glucocorticoid functions to inhibit the migration of immune cells into the brain or reduce edema, thereby inhibiting inflammation that occurred in the acute stage (see Immunology and Cell Biology. 76, 55-64; Annu. Rev. Immunol. 20, 125-163). Although glucocorticoid exhibits an excellent effect in the acute stage, it cannot prevent the progression of the disease in the disease-modifying therapy.
In the disease-modifying therapy, immunotherapy is performed in order to treat the disease and prevent the recurrence of the disease. Drugs approved by the US FDA for immunotherapy include interferon-beta (IFN-β), glatiramer acetate (GA), mitoxantrone and natalizumab. However, they show the following side effect (see N Engl J Med. 362, 456-458):
IFN-β, a drug that is currently most popularly used, has anti-inflammatory and antiviral effects and acts to inhibit the expression of antigens and prevent the activation of T cells. In addition, IFN-β activates co-stimulatory molecules to induce the apoptosis of self-reactive cells. However, IFN-β can be administered only by an intramuscular or subcutaneous route, and thus when it is administered for a long period of time, it causes erythema and edema at the injected site and involves side effects, including muscular pain, chills and autoimmune disease.
Mitoxantrone (novatrone) has very low molecular weight, and thus passes through the meninges to inhibit the proliferation of T cells, B cells and macrophages in the meninges and the antigen presenting function of antigen presenting cells (APCs), thereby alleviating the symptom of multiple sclerosis. However, mitoxantrone has a defect in that the dose should be limited, because it places a heavy burden on the heart.
Glatiramer acetate (GA) is an analogue of myelin basic protein (MBP). GA forms a GA/MHC complex when MBP binds to a HLA class II molecule, and thus it inhibits the activation of MBP-reactive T cells by competition with MBP when it binds to T cell receptor (TCR). GA has the effects of reducing the number of relapses of relapsing-remitting multiple sclerosis and alleviating the symptom of multiple sclerosis upon the relapse of multiple sclerosis, like IFN-β, but shows an increase frequency of development of permanent black holes in the central nervous system compared to IFN-β.
Natalizumab is a humanized monoclonal antibody that binds directly to the α4 subunit (CD49; adhesion molecule on the surface of leukocytes) of integrin VLA 4 (very late antigen 4) to prevent the binding between leukocytes and vascular endothelial cells, thereby preventing active T cells from entering the central nervous system. It shows excellent effects on relapsing-remitting multiple sclerosis, but causes a side effect of progressive multifocal leukoencephalopathy (PML) in 0.3-0.9% of the patients after 2 years of administration.
Fingolimod is a synthetic analogue of S1P (sphingosine 1-phosphate) receptor for myriocin and is the first orally administered drug recently approved by the US FDA.
Fingolimod acts to prevent activated lymphocytes from moving from secondary lymphoid tissues to the central nervous system by binding of S1PR to the surface of activated type 1 helper T cells. However, the drugs in developing were reported to have side effects, including infection, macular edema, headache, influenza, diarrhea, lumbago and an increase in liver enzyme (see Nat. Rev. Neurol. 7, 255-262; Nat Rev Drug Discov. 11, 909-925).
Thus, there is a need for the development of new drugs that can block the progression to secondary progressive multiple sclerosis while showing high therapeutic effects by short-term oral administration (see N Engl J Med. 362, 456-458).
Lymphoid Malignancy
As used herein, the term “lymphoid malignancy” refers to a tumor of lymphoid cells (B cells, T cells and NK/T cells) in bone marrow and lymphoid tissue. Lymphoid malignancy is largely classified into leukemia, lymphoma and multiple myeloma. Lymphoid leukemia is a blood tumor in which immature lymphocytes in bone marrow change to cancer cells that are accumulated in tissue and spread systemically through blood. Lymphoid leukemia is largely classified into acute lymphoid leukemia and chronic lymphoid leukemia. Lymphoma is a blood tumor in which lymphocytes in lymphoid tissue change to cancer cells that are accumulated in the tissue and spread to peripheral blood and bone marrow. It is classified into Hodgkin's lymphoma and non-Hodgkin's lymphoma. Multiple myeloma is a blood tumor in which plasma cells in peripheral lymphoid tissue change to cancer cells that are then accumulated in bone marrow (see J Clin Invest. 2012; 122:3396-3397; Blood. 1994; 84:1361-1392; Lancet. 2012; 380:848-857).
Treatment of lymphoid malignancy is performed by standard chemotherapy using a combination of cyclophosphamide, doxorubicin, vincristine and prednisone. With respect to the initial response effects of the drugs, the remission rate of adult patients is as high as about 85%, but the recurrence rate is high, and thus the 5-year disease-free survival is only 30-40%.
In addition, the drugs show a high risk of infection due to their high cytotoxicity and frequently cause side effects, including neurotoxicity, digestive problems and bleeding (see N Engl J Med. 1998; 339:21-26; N Engl J Med 2006; 354:166-78; Nat Rev Drug Discov. 2007; 6:149-165).
Recently, it has been reported that drugs having cytotoxic effects on specific cells also have anti-tumor effects when the same cells change to cancer cells. The B cell immunosuppressant ibrutinib that inhibits Bruton's tyrosine kinase (BTK), a signaling mediator of B cell receptor (BCR), was reported to have an anticancer effect against relapsing or drug-refractory B cell lymphoma. Bortezomib that is an inhibitor of NF-κB activity is used as an immunosuppressant for inhibiting memory T cells and B cells. Bortezomib was approved by the US FDA as a therapeutic agent for treating multiple sclerosis and has also recently been used in combination with ibrutinib for B cell lymphoma. Suberoylanilide hydroxamic acid (SAHA) that is histone deacetylase inhibitor (HDACi) is known to have an anticancer effect against cutaneous T cell lymphoma. Since the inhibitory effect of SAHA against graft-versus-host disease (GVHD) was recently found in animal models, SAHA has received new attention as an immunosuppressant (see Semin Cancer Biol. 2011 November; 21:335-46; Br J Haematol. 2013; 161:43-56; N Engl J Med. 2008; 359:906-917; Nat Rev Drug Discov. 2006; 5:769-784; J. Clin. Invest. 2008; 118:2562-2573). Thus, an immunosuppressive drug that targets specific immune cells can be clinically used as a new anticancer agent capable of specifically targeting a specific tumor.